Project Summary & Abstract In the US, it is estimated that at least 1% of children suffer from alcohol-related growth and neurocognitive defects associated with fetal alcohol spectrum disorders (FASDs). One of the major confounding elements in the study of this disorder is the enormous variation observed in both incidence and severity. The observed variance in FASD phenotypes indicates that multiple factors beyond the incidence of maternal drinking play a significant role in the development of this condition. Over the past 40 years, clinical studies have reported that 75% of FASD children have biological fathers who were either heavy drinkers or chronic alcoholics. However, the role of preconception male alcohol consumption in the development of FASD birth defects remains unexplored, largely due to the misconception that sperm do not transmit heritable information beyond the genetic code. Using a well-established mouse model, preconception male alcohol exposure has been associated with both prenatal and postnatal growth restriction, abnormalities in placental growth and sex-specific alterations in the long-term metabolic health of the offspring. The defects identified in these animal studies are similar to those described in long-term clinical studies of FASD children and reveal that paternal drug use is a significant modifier of offspring health. However, the molecular mechanisms by which paternal exposures prior to conception impact offspring development remain poorly defined. Further, the ability of paternal alcohol use to interact with gestational alcohol exposures and exacerbate the development FASDs has never been tested. This proposal responds to `PA-18-507 - Effects of In Utero Alcohol Exposure on Adult Health and Disease' and will define the basic fundamental mechanisms by which male preconception exposure to alcohol impacts the developmental program of the fetus and contributes to the incidence of FASD birth defects. Identifying a link between male alcohol use and a disorder that, until now, has been almost exclusively associated with the decisions of the birthmother, will hopefully prompt a shift of epidemiological perspectives that will more fully consider the lifestyle choices of the birthfather in the development of alcohol-related growth and neurocognitive defects.